This project studies the role of the endogenous opioid system (EOS) in humans. We have completed a dose-response study in normals of high doses of the opiate antagonist, naloxone (up to 4 mg/kg). Significant dose-dependent increases in physiologic (BP and respiratory rate) and hormonal variables (cortisol and growth hormone) were found suggesting progressive EOS blockade with increasing naloxone doses. Normals also experienced dysphoria at high naloxone doses suggesting EOS involvement in the regulation of mood in normals. In a separate double-blind study, high doses of naloxone produced a significant decrease in caloric intake in healthy, normal volunteers supporting hypothesized involvement of the EOS in eating behavior. In other work, we have studied the relationship between the hypothalamic-pituitary-adrenal axis and the EOS in depressive illness. As a continuation of our work demonstrating the responsiveness of the EOS to stress and involvement of the EOS in endogenous analgesic mechanisms, we have initiated a study of the analgesic and behavioral effects of synthetic Beta-endorphin administered by lumbar intrathecal route to patients with metastatic disease. In the two patients studied to date, intrathecally administered Beta-endorphin produced long-lasting analgesia. In addition, one of the patients experienced a unique behavioral syndrome characterized by hypomania/mania, psychosis and confusion. Further work is needed with this strategy to more fully evaluate analgesic potentials and the behavioral effects of this endogenous peptide when administered with access to the CNS.